Heterocyclic compounds and their therapeutic use

ABSTRACT

A compound of the formula  
                 
 
     wherein R 1  is C 1-3  alkyl optionally substituted with one or more fluorines;  
     R 2  is CH 2 OCH 3  or 2 or 3-tetrahydrofuranyl;  
     R 3  is a pyrazole, imidazole or isoxazole group of partial formula (A), (B) or (C)  
                 
 
     R 4  is C 1-3  alkyl; and  
     R 5  and R 6 , which may be the same or different, each represents C 1-3  alkyl, halogen, CF 3  or CN;  
     or a pharmaceutically-acceptable salt thereof.

FIELD OF THE INVENTION

[0001] The present invention relates to novel heterocyclic compounds andto their formulation and use as pharmaceuticals.

BACKGROUND OF THE INVENTION

[0002] The modes of action of phosphodiesterases and also tumournecrosis factor (TNF), and the therapeutic utilities of inhibitorsthereof, are described in WO-A-97/44337 and U.S. Pat. Nos. 5,925,636 and5,972,936, the contents of which are incorporated herein by reference.These reference describe benzofurans having such activity.

SUMMARY OF THE INVENTION

[0003] This invention provides novel compounds having therapeuticutility, in particular for the treatment of disease states associatedwith proteins which mediate cellular activity, for example by inhibitingTNF and/or PDE IV. According to the invention, the compounds are offormula (i):

[0004] wherein R₁ is C₁₋₃ alkyl optionally substituted with one or morefluorines;

[0005] R₂ is CH₂OCH₃ or 2 or 3-tetrahydrofuranyl;

[0006] R₃ is a pyrazole, imidazole or isoxazole group of partial formula(A), (B) or (C)

[0007] R₄ is C₁₋₃ alkyl; and

[0008] R₅ and R₆, which may be the same or different, each representsC₁₋₃ alkyl, halogen, CF₃ or CN,

[0009] or a pharmaceutically-acceptable salt thereof.

[0010] In summary, the compounds of the invention represent a selectionwithin the scope of WO-A-97/44337. The novel compounds have superior invivo activity.

[0011] This invention provides also a method for mediating or inhibitingthe enzymatic activity or catalytic activity of PDE IV in a mammal inneed thereof and for inhibiting the production of TNF in a mammal inneed thereof, which comprises administering to said mammal an effectiveamount of a compound of Formula (i) or a pharmaceutically-acceptablesalt thereof.

DESCRIPTION OF THE INVENTION

[0012] The term “C₁₋₃ alkyl” means methyl, ethyl, propyl or isopropyl.

[0013] One group of compounds of the invention is of formula (i) inwhich R₁ is CH₃ or CHF₂.

[0014] R₃ may in particular be a pyrazole of partial formula (A) or anisoxazole of partial formula (C). When R₃ is a pyrazole moiety, R₄ isespecially CH₃ and R₅ is particularly CN, CH₃, Cl or CF₃. Where R₃ is anisoxazole moiety, R₅ is especially CH₃, CF₃ or CN and R₆ is particularlyCH₃, CF₃ or CN.

[0015] The compounds of the Examples are especially preferred.

[0016] It will be appreciated by those skilled in the art that compoundsof formula (i) in which R₂ represents tetrahydrofuran contain a chiralcentre. This invention extends to both enantiomers and all mixturesthereof, including racemic mixtures.

[0017] Certain of the compounds of formula (i) which contain a basicgroup form acid addition salts. Suitable acid addition salts includepharmaceutically-acceptable inorganic salts such as the sulphate,nitrate, phosphate, borate, hydrochloride and hydrobromide, andpharmaceutically-acceptable organic acid addition salts such as acetate,tartrate, maleate, citrate, succinate, benzoate, ascorbate,methanesulphate, α-ketoglutarate, α-glycerophosphate andglucose-1-phosphate. The pharmaceutically-acceptable salts of thecompounds of formula (i) are prepared using conventional procedures.

[0018] Compounds of the invention may be prepared by reaction of anappropriate carboxylic acid of formula (ii) with a suitable amine offormula (iii) as described in WO 97/44337. Carboxylic acids of formula(ii) may be conveniently prepared from compounds of formula (iv) bybromination followed by palladium-catalysed carbonylation as describedin WO 97/44337. Amines of formula (iii) are either commerciallyavailable, previously described compounds, or are prepared usingstandard conditions known to those skilled in the art.

[0019] Compounds of formula (iv) in which R₁ represents methyl and R₂represents CH₂OCH₃ may be conveniently prepared from o-vanillin as shownbelow. o-Vanillin is treated with bromoacetaldehyde dimethyl acetal inthe presence of a base, such as potassium carbonate, in a suitablesolvent such as N,N-dimethylformamide, favourably at elevatedtemperature. The resultant acetal can then be cyclised, for example byheating in acetic acid, to provide 7-methoxybenzofuran-2-carbaldehyde.The aldehyde may be reduced using any suitable reducing agent known tothose skilled in the art, such as sodium borohydride. The resultantalcohol may be methylated using any appropriate methylating agent, suchas methyl iodide, in the presence of an appropriate base, such as sodiumhydride.

[0020] Compounds of formula (iv) in which R₁ represents methyl and R₂represents 3-tetrahydrofuranyl may be prepared from 7-methoxybenzofuranas depicted below. 7-Methoxybenzofuran may be deprotonated by treatmentwith any suitable base, such as butyllithium, and the resultant anionadded to tetrahydrofuran-3-one. The resultant alcohol may be convertedto a leaving group, such as a mesylate, and then eliminated. The alkenethus formed may be reduced using any suitable reducing agent, such asRaney nickel and hydrogen.

[0021] Compounds of formula (iv) in which R₁ represents methyl and R₂represents 2-tetrahydrofuranyl may be prepared from7-methoxybenzofuran-2-carbaldehyde as shown below. A suitably protectedGrignard reagent derived from 1,3-propanediol may be added to7-methoxybenzofuran-2-carbaldehyde, and the protecting group may then beremoved. A suitable protecting group may be tert-butyldimethylsilyl,which may be removed using any standard conditions known to thoseskilled in the art, for example tetrabutylammonium fluoride. Cyclisationof the resultant diol may be achieved using any appropriate conditions,such as p-toluenesulphonic acid and molecular sieves in a suitablesolvent such as dicloromethane.

[0022] Compounds of formula (iv) in which R₁ represents difluoromethoxymay be prepared by demethylation, and subsequent difluoromethylation, ofsuitable intermediates in which R₁ represents methyl. Such demethylationmay be carried out using any suitable conditions known to those skilledin the art. Suitable conditions include the use of ethane thiolate in anappropriate solvent, such as N,N-dimethylformamide, at a suitabletemperature. Suitable temperatures include elevated temperatures,favourably 140° C. Difluoromethylation of the resultant phenols may becarried out using any suitable conditions known to those skilled in theart. Suitable conditions include the use of chlorodifluoromethane and asuitable base in an appropriate solvent at an appropriate temperature.Favourably, the reaction is conducted in dioxane as solvent usingaqueous sodium hydroxide as base. Elevated temperatures, such as refluxtemperature, may be employed.

[0023] The invention includes the prevention and treatment ofTNF-mediated disease or disease states, by which is meant any and alldisease states in which TNF plays a role, either by production of TNFitself, or by TNF causing another cytokine to be released, such as butnot limited to IL-1 or IL-6. A disease state in which IL-1, forinstance, is a major component, and whose production or action isexacerbated or secreted in response to TNF, would therefore beconsidered a disease state mediated by TNF. As TNF-β (also known aslymphotoxin) has close structural homology with TNF-α (also known ascachectin), and since each induces similar biological responses andbinds to the same cellular receptor, both TNF-α and TNF-β are inhibitedby compounds of the present invention and thus are herein referred tocollectively as “TNF” unless specifically delineated otherwise.

[0024] PDE IV inhibitors are useful in the treatment of a variety ofallergic and inflammatory diseases, including: asthma, chronicbronchitis, atopic dermatitis, atopic eczema, urticaria, allergicrhinitis, allergic conjunctivitis, vernal conjunctivitis, inflammationof the eye, allergic responses in the eye, eosinophilic granuloma,psoriasis, Bechet's disease, erythematosis, anaphylactoid purpuranephritis, joint inflammation, arthritis, rheumatoid arthritis and otherarthritic conditions such as rheumatoid spondylitis and osteoarthritis,septic shock, ulcerative colitis, Crohn's disease, reperfusion injury ofthe myocardium and brain, chronic glomerulonephritis, endotoxic shockand adult respiratory distress syndrome. In addition, PDE IV inhibitorsare useful in the treatment of diabetes insipidus and conditionsassociated with cerebral metabolic inhibition, such as cerebralsenility, senile dementia (Alzheimer's disease), memory impairmentassociated with Parkinson's disease, depression and multi-infarctdementia. PDE IV inhibitors are also useful in conditions ameliorated byneuroprotectant activity, such as cardiac arrest, stroke andintermittent claudication. Additionally, PDE IV inhibitors could haveutility as gastroprotectants. A special embodiment of the therapeuticmethods of the present invention is the treatment of asthma.

[0025] The viruses contemplated for treatment herein are those thatproduce TNF as a result of infection, or those which are sensitive toinhibition, such as by decreased replication, directly or indirectly, bythe TNF inhibitors of Formula (i). Such viruses include, but are notlimited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza,adenovirus and the Herpes group of viruses, such as, but not limited to,Herpes zoster and Herpes simplex.

[0026] This invention more specifically relates to a method of treatinga mammal, afflicted with a human immunodeficiency virus (HIV), whichcomprises administering to such mammal an effective TNF inhibitingamount of a compound of Formula (i) or a pharmaceutically-acceptablesalt thereof.

[0027] The compounds of this invention may be also be used inassociation with the veterinary treatment of animals, other than humans,in need of inhibition of TNF production. TNF mediated diseases fortreatment, therapeutically or prophylactically, in animals includedisease states such as those noted above, but in particular viralinfections. Examples of such viruses include, but are not limited tofeline immunodeficiency virus (FIV) or other retroviral infection suchas equine infectious anaemia virus, caprine arthritis virus, visnavirus, maedi virus and other lentiviruses.

[0028] The compounds of this invention are also useful in treatingparasite, yeast and fungal infections, where such yeast and fungi aresensitive to upregulation by TNF or will elicit TNF production in vivo.A preferred disease state for treatment is fungal meningitis.

[0029] The compounds of formula (i) are preferably inpharmaceutically-acceptable form. By pharmaceutically-acceptable form ismeant, inter alia, a pharmaceutically-acceptable level of purityexcluding normal pharmaceutical additives such as diluents and carriers,and including no material considered toxic at normal dosage levels. Apharmaceutically-acceptable level of purity will generally be at least50% excluding normal pharmaceutical additives, preferably 75%, morepreferably 90% and still more preferably 95%. When used herein the term“pharmaceutically-acceptable” encompasses materials suitable for bothhuman and veterinary use.

[0030] A compound of formula (i) or where appropriate apharmaceutically-acceptable salt thereof and/or apharmaceutically-acceptable solvate thereof, may be administered per seor, preferably, as a pharmaceutical composition also comprising apharmaceutically-acceptable carrier.

[0031] Accordingly, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (i) or where appropriate apharmaceutically-acceptable salt thereof and/or apharmaceutically-acceptable solvate thereof, and apharmaceutically-acceptable carrier.

[0032] The active compound may be formulated for administration by anysuitable route, the preferred route depending upon the disorder forwhich treatment is required, and is preferably in unit dosage form or ina form that a human patient may administer to himself in a singledosage. Advantageously, the composition is suitable for oral, rectal,topical, parenteral administration or through the respiratory tract.Preparations may be designed to give slow release of the activeingredient.

[0033] The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. In addition to the treatment of warm-bloodedanimals such as mice, rats, horses, cattle, sheep, dogs, cats, etc, thecompounds of the invention are effective in the treatment of humans.

[0034] The compositions of the invention may be in the form of tablets,capsules, sachets, vials, powders, granules, lozenges, suppositories,reconstitutable powders, or liquid preparations such as oral or sterileparenteral solutions or suspensions. Topical formulations are alsoenvisaged where appropriate.

[0035] In order to obtain consistency of administration it is preferredthat a composition of the invention is in the form of a unit dose. Unitdose presentation forms for oral administration may be tablets andcapsules and may contain conventional excipients such as binding agents,for example syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; fillers for example microcrystalline cellulose,lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine;tabletting lubricants, for example magnesium stearate; disintegrants,for example starch, polyvinylpyrrolidone, sodium starch glycollate ormicrocrystalline cellulose; or pharmaceutically-acceptable wettingagents such as sodium lauryl sulphate.

[0036] Solid oral compositions may be prepared by conventional methodsof blending, filling, tabletting or the like. Repeated blendingoperations may be used to distribute the active agent throughout thosecompositions employing large quantities of fillers.

[0037] Such operations are of course conventional in the art. Thetablets may be coated according to methods well known in normalpharmaceutical practice, in particular with an enteric coating.

[0038] Oral liquid preparations may be in the form of, for example,emulsions, syrups or elixirs, or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assuspending agents, for example sorbitol, syrup, methyl cellulose,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel, hydrogenated edible fats; emulsifying agents, for examplelecithin, sorbitan monooleate, or acacia, non-aqueous vehicles (whichmay include edible oils), for example almond oil, fractionated coconutoil, oily esters such as esters of glycerine, propylene glycol, or ethylalcohol; preservatives, for example methyl or propyl p-hydroxybenzoateor sorbic acid; and if desired conventional flavouring or colouringagents.

[0039] Compositions may also suitably be presented for administration tothe respiratory tract as a snuff or an aerosol or solution for anebuliser, or as a microfine powder for insufflation, alone or incombination with an inert carrier such as lactose. In such a case theparticles of active compound suitably have diameters of less than 50 μm,such as from 0.1 to 50 μm, preferably less than 10 μm, for example from1 to 10 μm, 1 to 5 μm or from 2 to 5 μm. Where appropriate, smallamounts of other anti-asthmatics and bronchodilators for examplesympathomimetic amines such as isoprenaline, isoetharine, salbutamol,phenylephrine and ephedrine; corticosteroids such as prednisolone andadrenal stimulants such as ACTH may be included.

[0040] For parenteral administration, fluid unit dosage forms areprepared utilizing the compound and a sterile vehicle, and, depending onthe concentration used, can be either suspended or dissolved in thevehicle. In preparing solutions, the compound can be dissolved in waterfor injection and filter-sterilised before filling into a suitable vialor ampoule and sealing.

[0041] Advantageously, adjuvants such as a local anaesthetic, apreservative and buffering agents can be dissolved in the vehicle. Toenhance the stability, the composition can be frozen after filling intothe vial and the water removed under vacuum. Parenteral suspensions areprepared in substantially the same manner, except that the compound issuspended in the vehicle instead of being dissolved, and sterilisationcannot be accomplished by filtration. The compound can be sterilised byexposure to ethylene oxide before suspending in the sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

[0042] The compositions may contain from 0.1% to 99% by weight,preferably from 10-60% by weight, of the active material, depending onthe method of administration.

[0043] Compounds of formula (i), or if appropriate apharmaceutically-acceptable salt thereof and/or apharmaceutically-acceptable solvate thereof, may also be administered asa topical formulation in combination with conventional topicalexcipients.

[0044] Topical formulations may be presented as, for instance,ointments, creams or lotions, impregnated dressings, gels, gel sticks,spray and aerosols, and may contain appropriate conventional additivessuch as preservatives, solvents to assist drug penetration andemollients in ointments and creams. The formulations may containcompatible conventional carriers, such as cream or ointment bases andethanol or oleyl alcohol for lotions.

[0045] Suitable cream, lotion, gel, stick, ointment, spray or aerosolformulations that may be used for compounds of formula (i) or ifappropriate a pharmaceutically-acceptable salt thereof, are conventionalformulations well known in the art, for example, as described instandard text books such as Harry's Cosmeticology published by LeonardHill Books, Remington's Pharmaceutical Sciences, and the British and USPharmacopoeias.

[0046] Suitably, the compound of formula (i), or if appropriate apharmaceutically-acceptable salt thereof, will compromise from about 0.5to 20% by weight of the formulation, favourably from about 1 to 10%, forexample 2 to 5%.

[0047] The dose of the compound used in the treatment of the inventionwill vary in the usual way with the seriousness of the disorders, theweight of the sufferer, and the relative efficacy of the compound.However, as a general guide suitable unit doses may be 0.1 to 1000 mg,such as 0.5 to 200, 0.5 to 100 or 0.5 to 10 mg, for example 0.5, 1, 2,3, 4 or 5 mg; and such unit doses may be administered more than once aday, for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2times per day, so that the total daily dosage for a 70 kg adult is inthe range of about 0.1 to 1000 mg, that is in the range of about 0.001to 20 mg/kg/day, such as 0.007 to 3, 0.007 to 1.4, 0.007 to 0.14 or 0.01to 0.5 mg/kg/day, for example 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or0.2 mg/kg/day, and such therapy may extend for a number of weeks ormonths.

Assay Methods

[0048] The assays used to confirm the phosphodiesterase IV inhibitoryactivity of compounds of formula (I) are standard assay procedures asdisclosed by Schilling et al, Anal. Biochem. 216:154 (1994), Thompsonand Strada, Adv. Cycl. Nucl. Res. 8:119 (1979) and Gristwood and Owen,Br. J. Pharmacol. 87:91P (1986).

[0049] Compounds of formula (i) have exhibited activity at levelsconsistent with those believed to be useful in treatingphosphodiesterase IV related disease states in those assays.

[0050] The ability of compounds of formula (i) to inhibit TNF productionin human peripheral blood mononuclear cells (PMBC's) is measured asfollows. PMBC's are prepared from freshly taken blood or “Buffy coats”by standard procedures. Cells are plated out in RPMI1640+1% foetal calfserum in the presence and absence of inhibitors. LPS (Lipopolysaccharide(endotoxin); 100 ng/ml) is added and cultures are incubated for 22 h at37° C. in an atmosphere of 95% air/5% CO₂. Supernatants are tested forTNFα by ELISA (Enzyme linked immunosorbent assay) using commerciallyavailable kits.

[0051] Activity in a guinea pig lung model is measured using theprocedures described by Mauser et al, Am. Rev. Respir. Dis. 148:1623(1993), and Am. J. Respir. Crit. Care Med. 152:467 (1995).

[0052] The compound of Example 2 of WO-A-97/44337 exhibits 41%inhibition of eosinophilia in the guinea pig model when dosed at 30mg/kg. Example 10 herein (representative of the present invention)achieves 35% inhibition when dosed at 3 mg/kg.

[0053] The following Examples illustrate the invention.

[0054] Intermediate 1 2-(2-Formyl-6-methoxyphenoxy)acetaldehyde,dimethyl acetal

[0055] o-Vanillin (20 g) and potassium carbonate (18 g) were stirred inN,N-dimethylformamide (80 ml) at room temperature for 30 minutes.Bromoacetaldehyde dimethyl acetal (24 g) was added dropwise ensuringthat the temperature did not rise above 50° C. The mixture was thenheated at reflux for 4 hours then cooled to room temperature. Diethylether (30 ml) was added and the mixture was filtered. The solid waswashed with ether (2×30 ml) and the combined organic phases wereconcentrated in vacuo to give the title compound (33 g) as a green oil.

[0056] TLC R_(f)0.66 (50% ethyl acetate in hexane).

[0057] Intermediate 2 7-Methoxybenzofuran-2-carbaldehyde

[0058] 2-(2-Formyl-6-methoxyphenoxy)acetaldehyde, dimethyl acetal (31 g)was heated to reflux in glacial acetic acid (120 ml) overnight. Themixture was then cooled and the solvent removed in vacuo to give a redoil. Purification by Kugelrohr distillation gave the title compound (17g) as a pale yellow oil which solidified on standing.

[0059] TLC R_(f) 0.71 (dichloromethane).

[0060] Intermediate 3 7-Methoxybenzofuran-2-yl-methanol

[0061] Sodium borohydride (0.462 g) was added in one portion to astirred solution of 7-methoxybenzofuran-2-carbaldehyde (2.15 g) inmethanol (50 ml) at room temperature and the reaction was stirred for 3hours. The reaction mixture was then diluted with water (100 ml) andextracted with dichloromethane (3×30 ml). The organic extracts werecombined, washed with water (30 ml), dried over magnesium sulphate,filtered and the solvent removed in vacuo to afford the title compound(2.10 g) as a pale orange liquid.

[0062] TLC R_(f) 0.51 (2% methanol in dichloromethane).

[0063] Intermediate 4 7-Methoxy-2-methoxymethylbenzofuran

[0064] Sodium hydride (3.82 g, 60% in mineral oil) was added to asolution of 7-methoxybenzofuran-2-ylmethanol (11.21 g) in drytetrahydrofuran (300 ml) under an atmosphere of dry nitrogen at roomtemperature. After 10 minutes iodomethane (15.67 ml) was added and thereaction was left to stir overnight. The solvent was removed in vacuoand the residue partitioned between ethyl acetate (100 ml) and water (50ml). The organic extract was washed with water (50 ml), followed bybrine (50 ml), dried over magnesium sulphate, filtered and the solventremoved in vacuo to afford the title compound (13.32 g) as a yellow oil.

[0065] TLC R_(f) 0.70 (50% ethyl acetate in hexane).

[0066] Intermediate 54-(tert-Butyldimethylsilanyloxy)-1-(7-methoxybenzofuran-2-yl)-butan-1-ol

[0067] A suspension of dried magnesium turnings (0.42 g) in anhydroustetrahydrofuran (20 ml) was treated with 2 ml of(3-Bromopropoxy)-tert-butyldimethylsilane (4.4 g) in anhydroustetrahydrofuran (10 ml) at room temperature under a dry nitrogenatmosphere. Initiation was achieved by the addition of catalytic iodineand warming to 80° C. The remaining solution (8 ml) was then addedcarefully. The reaction was cooled to −5° C. and a solution of7-methoxybenzofuran-2-carbaldehyde (3 g) in anhydrous tetrahydrofuran(20 ml) was added carefully. After stirring at ambient temperatureovernight the solvent was removed in vacuo. The residue was partitionedbetween ethyl acetate (100 ml) and saturated aqueous ammonium chloridesolution (100 ml). The organic extract was dried over magnesiumsulphate, filtered and preadsorbed onto silica. Purification by columnchromatography on silica eluting with 10% ethyl acetate in hexaneafforded the title compound as a yellow oil (4.88 g).

[0068] TLC R_(f) 0.75 (20% ethyl acetate).

[0069] Intermediate 6 1-(7-Methoxybenzofuran-2-yl)-butane-1,4-diol

[0070] Tetrabutylammonium fluoride (1 2 ml, 1M in tetrahydrofuran) wasadded to a stirred solution of4-(tert-butyldimethylsilanyloxy)-1-(7-methoxybenzofuran-2-yl)-butan-1-ol(4 g) in tetrahdrofuran (50 ml) at 0° C. After stirring cooled for 2hours the reaction was warmed to room temperature and allowed to stirfor a further 1 hour. The solvent was removed in vacuo and the residuepartitioned between ethyl acetate (100 ml) and water (50 ml). Theorganic extract was dried over magnesium sulphate, filtered andpreadsorbed onto silica. Purification by column chromatography on silicaeluting with ethyl acetate yielded the title compound as a tan oil (2.34g).

[0071] TLC R_(f) 0.15 (50% ethyl acetate in hexane).

[0072] Intermediate 7 7-Methoxy-2-(tetrahydrofuran-2-yl)-benzofuran

[0073] A solution of 1-(7-methoxybenzofuran-2-yl)-butane-1,4-diol (0.88g) was treated with p-toluenesulfonic acid monohydrate (10 mg) and 3Åmolecular sieves in dichloromethane (10 ml) at ambient temperature.After stirring for 1 hour the solvent was removed in vacuo. The residuewas purified by column chromatography on silica eluting with 20% ethylacetate in hexane to give the title compound as a yellow oil (0.58 g).

[0074] TLC R_(f) 0.35 (20% ethyl acetate in hexane).

[0075] Intermediate 8 3-(7-Methoxybenzofuran-2-yl)-tetrahydrofuran-3-ol

[0076] Methyl sulfoxide (1.16 ml) was added dropwise to a stirredsolution of oxalyl chloride (0.71 ml) in dry dichloromethane (15 ml) at−60° C. under an inert atmosphere. After stirring at this temperaturefor 30 minutes a solution of 3-hydroxytetrahydrofuran (0.55 ml) in drydichloromethane was added carefully. After a further 30 minutestriethylamine was added dropwise and the reaction allowed to warm toroom temperature. The reaction was poured onto water (40 ml) andextracted with dichloromethane (30 ml). The organic phase was washedwith water (50 ml), brine (2×50 ml) and saturated aqueous sodiumhydrogen carbonate solution (2×50 ml). After drying over magnesiumsulphate the solvent was removed in vacuo to affordtetrahydro-furan-3-one as a yellow gum (0.19 g). n-Butyllithium (0.72ml, 1.6M in hexanes) was added dropwise to a stirred solution of7-methoxybenzofuran (0.15 g) in dry tetrahydrofuran (5 ml) at −78° C.under a dry nitrogen atmosphere. After stirring for 20 minutes asolution of tetrahydrofuran-3-one (90 mg) in dry tetrahydrofuran (2 ml)was added carefully. After stirring for a further 15 minutes at −78° C.the reaction was allowed to warm to room temperature. The reaction wascarefully quenched with water and the solvent removed in vacuo. Theresidue was partitioned between ethyl acetate (2×15 ml) and water (15ml). The combined organic extracts were dried over magnesium sulphate,filtered and concentrated in vacuo. The residue was purified by columnchromatography on silica eluting with 50% ethyl acetate in hexane togive the title compound as an orange gum (64 mg).

[0077] TLC R_(f)0.37 (50% ethyl acetate in hexane).

[0078] Intermediate 9 7-Methoxy-2-(tetrahydrofuran-3-yl)-benzofuran

[0079] Triethylamine (0.19 ml) was added to a stirred solution of3-(7-methoxybenzofuran-2-yl)-tetrahydrofuran-3-ol (0.15 g) in drydichloromethane (8 ml) at room temperature under a dry nitrogenatmosphere. Methanesulfonyl chloride (0.08 ml) was then added followedby a catalytic amount of 4-(dimethylamino)pyridine. After stirring atroom temperature overnight the solvent was removed in vacuo. The residuewas purified by column chromatography on silica eluting with 50% ethylacetate in hexane to give a mixture of2-(4,5-dihydrofuran-3-yl)-7-methoxybenzofuran and2-(2,5-dihydrofuran-3-yl)-7-methoxybenzofuran (85 mg) as a yellow solid.

[0080] A solution of the alkene mixture (85 mg) in ethanol (10 ml) wastreated with Raney Nickel and hydrogenated at atmospheric pressure for 1hour. The reaction mixture was filtered through celite and the solventwas removed in vacuo to give the title compound as a white solid (80mg).

[0081] TLC R_(f) 0.49 (33% ethyl acetate in hexane).

[0082] Intermediate 10 2-(Tetrahydrofuran-3-yl)-benzofuran-7-ol

[0083] Sodium hydride (0.19 g, 60% in mineral oil) was added to astirred solution of ethane thiol (0.34 ml) in N,N-dimethylformamide (6ml) at room temperature under a dry nitrogen atmosphere. After stirringfor 15 minutes 7-methoxy-2-(tetrahydrofuran-3-yl) benzofuran (0.5 g) inN,N-dimethylformamide (6 ml) was added and the reaction heated to 140°C. for 2 hours. After cooling to room temperature the solvent wasremoved in vacuo. The residue was partitioned between ethyl acetate (50ml) and water (50 ml). The organic extract was dried over magnesiumsulphate, filtered and preadsorbed onto silica. Purification by columnchromatography on silica eluting with 50% ethyl acetate in heptaneafforded the title compound as a brown oil (0.37 g).

[0084] TLC R_(f) 0.38 (50% ethyl acetate in heptane).

[0085] Intermediate 11tert-Butyldimethyl-[2-(tetrahydrofuran-3-yl)-benzofuran-7-yloxy]-silane

[0086] Sodium hydride (80 mg, 60% dispersion in mineral oil) was addedto a stirred solution of 2-(tetrahydrofuran-3-yl)-benzofuran-7-ol (0.37g) in dry tetrahydrofuran (10 ml) at room temperature under a drynitrogen atmosphere. After stirring for 10 minutestert-butyldimethylsilyl chloride (0.27 g) was added and the reactionstirred for 90 minutes. The reaction mixture was partitioned betweenethyl acetate (30 ml) and water (2×25 ml). The combined aqueous washingswere extracted with ethyl acetate (30 ml). The organic extracts werecombined, dried over magnesium sulphate, filtered and concentrated invacuo to give the title compound as a yellow oil (0.58 g).

[0087] TLC R_(f) 0.7 (50% ethyl acetate in heptane).

[0088] Intermediate 12 4-Bromo-7-methoxy-2-methoxymethylbenzofuran

[0089] A solution of 7-methoxy-2-methoxymethylbenzofuran (13.32 g) inacetonitrile (500 ml) was stirred at room temperature.N-bromosuccinimide (11.04 g) was added and stirring continued for 2 daysafter which the solvent was removed in vacuo. The resulting oil waspartitioned between ethyl acetate (100 ml) and sodium metasulfitesolution (50 ml), the organic extract washed with more sodiummetasulfite solution (2×50 ml), followed by brine (50 ml). The organiclayer was separated, dried over magnesium sulphate, filtered and thesolvent removed in vacuo to afford the title compound as a yellow oil(18.61 g).

[0090] TLC R_(f) 0.73 (50% ethyl acetate in hexane).

[0091] The following compounds were prepared in a similar manner.

[0092] Intermediate 134-Bromo-7-methoxy-2-(tetrahydrofuran-2-yl)-benzofuran

[0093] Starting from 7-methoxy-2-(tetrahydrofuran-2-yl)-benzofuran (0.58g). The title compound was obtained as a yellow oil (0.8 g).

[0094] TLC R_(f) 0.35 (20% ethyl acetate in hexane).

[0095] Intermediate 144-Bromo-7-methoxy-2-(tetrahydrofuran-3-yl)-benzofuran

[0096] Starting from 7-methoxy-2-(tetrahydrofuran-3-yl)-benzofuran (80mg). The title compound was obtained as a brown oil (65 mg).

[0097] TLC R_(f) 0.46 (33% ethyl acetate in hexane).

[0098] Intermediate 15[4-Bromo-2-(tetrahydrofuran-3-yl)-benzofuran-7-yloxy]-tert-butyldimethylsilane

[0099] Starting fromtert-Butyldimethyl-[2-(tetrahydrofuran-3-yl)-benzofuran-7-yloxy]-silane(0.59 g). Purification by column chromatography on silica eluting with20% ethyl acetate in heptane afforded the title compound as a brown oil(0.31 g).

[0100] TLC R_(f) 0.48 (20% ethyl acetate in heptane).

[0101] Intermediate 16 4-Bromo-2-(tetrahydrofuran-3-yl)-benzofuran-7-ol

[0102] Tetrabutylammonium fluoride (8.1 ml, 1M in tetrahydrofuran) wasadded to a stirred solution of[4-bromo-2-(tetrahydrofuran-3-yl)-benzofuran-7-yloxy]-tert-butyldimethylsilane(2.69 g) in dry tetrahydrofuran (80 ml) at 0° C. under a dry nitrogenatmosphere. After stirring at this temperature for 45 minutes thesolvent was removed in vacuo. The residue was partitioned between ethylacetate (75 ml) and water (75 ml). The organic extract was dried overmagnesium sulphate, filtered and concentrated in vacuo. Purification bycolumn chromatography on silica eluting with 50% ethyl acetate inheptane afforded the title compound as a clear oil (1 g).

[0103] TLC R_(f) 0.39 (50% ethyl acetate in heptane).

[0104] Intermediate 17 4-Bromo-2-methoxymethylbenzofuran-7-ol

[0105] To a stirred solution of sodium hydride (334 mg, 60% in mineraloil) in dry N,N-dimethylformamide (25 ml) under an atmosphere of drynitrogen at room temperature was added dropwise ethane thiol (0.586 ml).After stirring for 20 minutes a solution of4-bromo-7-methoxy-2-methoxymethylbenzofuran(2.04 g) inN,N-dimethyl-formamide (7 ml) was added dropwise and the reactionmixture was heated at 160° C. for 2 hours. The reaction was cooled andthe solvent removed in vacuo. The residue was dissolved in ethyl acetate(70 ml) and washed with ammonium chloride solution (70 ml). The organicextract was dried over magnesium sulphate, filtered and the solventremoved in vacuo. Purification by column chromatography on silicaeluting with 50% ethyl acetate in hexane afforded the title compound asa white solid (1.21 g).

[0106] TLC R_(f)0.65 (50% ethyl acetate in hexane).

[0107] Intermediate 184-Bromo-7-difluoromethoxy-2-methoxymethylbenzofuran

[0108] To a solution of 4-bromo-2-methoxymethylbenzofuran-7-ol in1,4-dioxane (25 ml) heated to 100° C. was added dropwise a solution ofsodium hydroxide (0.76 g) in water (2 ml). Chlorodifluoromethane wasbubbled through the reaction mixture for 2 hours after which it wasallowed to cool to room temperature and the organic solvent removed invacuo. The resulting aqueous slurry was extracted with ethyl acetate(3×25 ml). The organic extracts were dried over magnesium sulphate,filtered and the solvent removed in vacuo. Purification by columnchromatography on silica eluting with 20% ethyl acetate in hexaneafforded the title compound as an off-white solid (1.24 g).

[0109] TLC R_(f) 0.73 (20% ethyl acetate in hexane).

[0110] The following compound was prepared in a similar manner.

[0111] Intermediate 194-Bromo-7-difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran

[0112] Starting from 4-bromo-2-(tetrahydrofuran-3-yl)-benzofuran-7-ol (1g). Purification by column chromatography on silica eluting with 30%ethyl acetate in heptane gave the title compound as a pale yellow solid(0.8 g).

[0113] TLC R_(f) 0.64 (50% ethyl acetate in heptane).

[0114] Intermediate 20 7-Methoxy-2-methyoxymethylbenzofuran-4-carboxylicacid

[0115] 4-Bromo-7-methoxy-2-methoxymethylbenzofuran (18.61 g), Pplladuimchloride (3.09 g), bis-diphenylphosphinopropane (6.60 g), triethylamine(49.65 ml), tetrahydrofuran (200 ml), and water (50ml) were combined ina Parr pressure reactor. The vessel was purged with carbon monoxide 3times before being charged with carbon monoxide at 140 psi. The vesselwas then heated at 90° C. for 3 days before cooling and release of thepressure. The reaction mixture was concentrated in vacuo and the residuetaken up in 2N sodium hydroxide solution (250 ml). The reaction mixturewas washed with ethyl acetate (2×300 ml) and then the aqueous layer wasacidified to pH 5 with 10N hydrochloric acid. The resulting mixture wasextracted with dicloromethane (2×100 ml), the combined organic extractsdried over magnesium sulphate, filtered and the solvent removed in vacuoto afford the title compound as a yellow solid (14.24 g).

[0116] TLC R_(f) 0.31 (50% ethyl acetate in hexane).

[0117] The following compounds were prepared in a similar manner.Intermediate 21 7-Difluoromethoxy-2-methoxymethylbenzofuran-4-carboxylicacid

[0118] Starting from 4-bromo-7-difluoromethoxy-2-methoxymethylbenzofuran(1.24 g). After carbonylation the reaction mixture was concentrated invacuo to remove organic solvent and the subsequent aqueous residueextracted with dichloromethane (50 ml). The aqueous layer was acidifiedto pH4 with glacial acetic acid and extracted with ethyl acetate (2×100ml). The combined organic extracts were dried over magnesium sulphate,filtered and the solvent removed in vacuo to afford the title compoundas a white solid.

[0119] TLC R_(f) 0.63 (50% ethyl acetate in hexane).

[0120] Intermediate 227-Methoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic acid

[0121] Starting from4-bromo-7-methoxy-2-(tetrahydrofuran-3-yl)-benzofuran (1.9 g). The titlecompound was obtained as an orange solid (1.18 g).

[0122] TLC R_(f) 0.58 (ethyl acetate).

[0123] Intermediate 237-Difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic acid

[0124] Starting from4-bromo-7-difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran (0.8 g).The title compound was obtained as a cream solid (0.72 g).

[0125] TLC R_(f) 0.24 (50% ethyl acetate in heptane).

[0126] Intermediate 247-Methoxy-2-(tetrahydrofuran-2-yl)-benzofuran-4-carboxylic acid

[0127] Starting from4-bromo-7-methoxy-2-(tetrahydrofuran-2-yl)-benzofuran (0.8 g). The titlecompound was obtained as an off white solid (0.63 g).

[0128] TLC R_(f) 0.13 (20% ethyl acetate in hexane).

[0129] Intermediate 25 7-Methoxy-2-methoxymethylbenzofuran-4-carboyxlicacid 4-nitrophenyl ester

[0130] 7-Methoxy-2-methyoxymethylbenzofuran-4-carboxylic acid (0.42 g),p-nitrophenol (0.29 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.4 g) and 4-dimethylaminopyridine (catalytic) in drydichloromethane (30 ml) were stirred overnight at room temperature. Thereaction mixture was washed with water (40 ml) and the aqueous layerextracted with dichloromethane (40 ml). The organic extracts werecombined, washed with water (80 ml), dried over magnesium sulphate,filtered and the solvent removed in vacuo. The residue was trituratedwith ethyl acetate and diethyl ether to afford the title compound as acream solid (0.42 g).

[0131] TLC R_(f) 0.61 (50% ethyl acetate in hexane).

[0132] The following compounds were prepared in a similar manner.

[0133] Intermediate 267-Difluoromethoxy-2-methoxymethylbenzofuran-4-carboxylic acid4-nitrophenyl ester

[0134] Starting from7-difluoromethoxy-2-methoxymethylbenzofuran-4-carboxylic acid (118 mg).Purification by trituration with diethyl ether afforded the titlecompound as a pale yellow solid (83 mg).

[0135] TLC R_(f) 0.54 (50% ethyl acetate in heptane).

[0136] Intermediate 277-Methoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic acid4-nitrophenyl ester

[0137] Starting from7-methoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic acid (1.16g). The title compound was obtained as a brown solid (1.76 g).

[0138] TLC R_(f) 0.82 (5% methanol in dichloromethane).

[0139] Intermediate 287-Difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic acid4-nitrophenyl ester

[0140] Starting from7-difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic acid(0.3 g). Purification by column chromatography on silica eluting with50% ethyl acetate in heptane gave the title compound as a white solid(0.38 g).

[0141] TLC R_(f) 0.55 (50% ethyl acetate in heptane).

[0142] Intermediate 297-Methoxy-2-(tetrahydrofuran-2-yl)-benzofuran-4-carboxylic acid4-nitrophenyl ester

[0143] Starting from7-methoxy-2-(tetrahydrofuran-2-yl)-benzofuran-4-carboxylic acid (0.3 g).Purification by column chromatography on silica eluting with 50% ethylacetate in heptane gave the title compound as a cream solid (0.37 g).

[0144] TLC R_(f) 0.48 (50% ethyl acetate in heptane).

[0145] Intermediate 30 4-Chloro-2-methyl-2H-pyrazol-3-ylamine

[0146] To a solution of 2-methyl-2H-pyrazol-3-ylamine (0.30 g) in conc.hydrochloric acid (4 ml) heated to 85° C. was added dropwise hydrogenperoxide (0.67 ml of a 30% solution in water). Heating continued for 60mins. After cooling to 0° C. the solution was taken to pH 11 using46/48% w/w sodium hydroxide solution. The solid formed was filtered offand the filtrate extracted with ethyl acetate (4×50 ml). The combinedorganic layers were dried over magnesium sulphate, filtered andconcentrated in vacuo. The resulting product was combined with thepreviously collected product to afford the title compound as a brownsolid (0.13 g).

[0147] TLC R_(f) 0.50 (10% methanol in dichloromethane).

EXAMPLE 1 7-Methoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylicacid (3,5-dimethylisoxazol-4-yl)-amide

[0148] To a stirred solution of 3,5-dimethylisoxazol-4-ylamine (88 mg)in N,N-dimethylformamide (7 ml) under an atmosphere of dry nitrogen atroom temperature was added sodium bis(trimethylsilyl)amide (0.78 ml,1.0M solution in tetrahydrofuran). The reaction was stirred for 5minutes. 7-Methoxy-2-(tetrahydro-furan-3-yl)-benzofuran-4-carboxylicacid 4-nitrophenyl ester (200 mg) was then added and stirring continuedfor 15 minutes. Water (1 ml) was added and the solvent was removed invacuo. The resulting residue was purified by column chromatography onsilica eluting with 50% ethyl acetate in heptane followed by triturationwith diethyl ether affording the title compound as a cream solid (52mg).

[0149] TLC R_(f) 0.60 (50% ethyl acetate in heptane).

[0150] Mp 183.5-185.2° C.

[0151] The following compounds were prepared in a similar manner.

EXAMPLE 27-Difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic acid(4-cyano-2-methyl-2-H-pyrazol-3-yl)-amide

[0152] Prepared from7-difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic acid4-nitrophenyl ester (380 mg) and5-amino-1-methyl-1-H-pyrazole-4-carbonitrile (220 mg). The reaction wasstirred for 2 hours at room temperature. Water (1 ml) was added and thesolvent removed in vacuo. The residue was dissolved in ethyl acetate (50ml) and washed with water (2×40 ml), followed by 1N hydrochloric acid(40 ml). The organic extract was dried over magnesium sulphate, filteredand preadsorbed onto silica. Purification by column chromatography onsilica eluting with 70% ethyl acetate in heptane, followed bytrituration with diethyl ether afforded the title compound as a whitesolid (170 mg).

[0153] TLC R_(f) 0.63 (ethyl acetate).

[0154] Mass spectrum m/z 403 [M+H].

EXAMPLE 3 7-Methoxy-2-methoxymethylbenzofuran-4-carboxylic acid(5cyano-3-methyl-3H-imidazol-4-yl)-amide

[0155] Prepared from 7-methoxy-2-methoxymethylbenzofuran-4-carboxylicacid 4-nitrophenyl ester (250 mg) and5-amino-1-methyl-1-H-imidazole-4-carbonitrile (171 mg). The reaction wasstirred for 1 hour and 40 minutes. Water (1 ml) was added and thesolvent removed in vacuo. Purification by column chromatography onsilica eluting with 10% methanol in dichloromethane afforded the titlecompound as a pale yellow solid (178 mg).

[0156] TLC R_(f)0.35 (10% methanol in dichloromethane).

[0157] Mass spectrum m/z 339[M−H]

EXAMPLE 4 7-Difluoromethoxy-2-methoxymethylbenzofuran-4-carboxylic acid(4-cyano-2-methyl-2-pyrazol-3-yl)-amide

[0158] Prepared from7-difluoromethoxy-2-methoxymethylbenzofuran-4-carboxylic acid4-nitrophenyl ester (83 mg) and5-amino-1-methyl-1-H-pyrazole-4-carbonitrile (52 mg) at 0° C. Thereaction was stirred for 90 minutes at room temperature. Water (1 ml)was added and the solvent removed in vacuo. Purification by columnchromatography on silica eluting with 70% ethyl acetate in heptane,followed by trituration with diethyl ether afforded the title compound(21 mg).

[0159] TLC R_(f)0.35 (70% ethyl acetate in heptane).

[0160] Mp 118-120° C.

EXAMPLE 5 7-Methoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylicacid (4-cyano-2-methyl-2-pyrazol-3-yl)-amide

[0161] Prepared from 7-methoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic acid 4-nitrophenyl ester (200 mg) and5-amino-1-methyl-1-H-pyrazole-4-carbonitrile (127 mg) at 0° C. Thereaction was stirred for 60 minutes at room temperature. Water (1 ml)was added and the solvent removed in vacuo. Purification by columnchromtography on silica eluting with 10% methanol in dichloromethanefollowed by gradient preparative HPLC on a Phenomenex LUNA(2)™ C18column eluting with 0.05% trifluoroacetic acid in 20%-65% acetonitrilein water afforded the title compound (19 mg) as a white solid.

[0162] TLC R_(f) 0.47 (ethyl acetate).

[0163] Mp 186-188.8° C.

EXAMPLE 6 7-Methoxy-2-(tetrahydrofuran-2-yl)-benzofuran-4-carboxylicacid (4-cyano-2-methyl-2-pyrazol-3-yl)-amide

[0164] Prepared from7-methoxy-2-(tetrahydrofuran-2-yl)-benzofuran-4-carboxylic acid4-nitrophenyl ester (370 mg) and 5-amino-1-methyl-1-H-pyrazole-4carbonitrile (122 mg). The residue obtained from removing solvent invacuo was dissolved in ethyl acetate (50 ml) and washed with water (50ml) followed 1N hydrochloric acid (25 ml). The organic extract was driedover magnesium sulphate, filtered and preadsorbed onto silica.Purification by column chromatography on silica eluting with ethylacetate afforded the title compound as a white solid (166 mg).

[0165] TLC R_(f)0.56 (ethyl acetate).

[0166] Mp 114.5-116°0 C.

EXAMPLE 7 7-Methoxy-2-methoxymethylbenzofuran-4-carboxylic acid(4-cyano-2-methyl-2-pyrazol-3-yl)-amide

[0167] Oxalyl chloride (0.07 ml) was added to a stirred solution of7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid (100 mg) in drydichloromethane (20 ml) at room temperature under a dry nitrogenatmosphere. N,N-dimethylformamide (catalytic amount) was added and thereaction allowed to stir overnight. The solvent was removed in vacuo toafford the corresponding acid chloride as an oily yellow solid.

[0168] To a stirred solution of5-amino-1-methyl-1-H-pyrazole-4-carbonitrile (155 mg) inN,N-dimethylformamide (7 ml) under an atmosphere of nitrogen at 0° C.was added sodium hydride (51 mg, 60% dispersion in mineral oil). Thereaction was stirred at 0° C. for 5 minutes. A solution of the acidchloride in N,N-dimethylformamide (8 ml) was added and the reactionstirred at room temperature for 2 hours. Water (1 ml) was added and thesolvent removed in vacuo. Purification by column chromatography onsilica eluting with 1% methanol in dichloromethane followed bytrituration with 50% diethyl ether in hexane afforded the title compoundas a pale yellow solid (4 mg).

[0169] TLC R_(f) 0.52 (10% methanol in dichloromethane).

[0170] Mass spectrum m/z 339[M−H]

EXAMPLE 87-Difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic acid(3,5-dimethylisoxazol-4-yl)-amide

[0171] Oxalyl chloride (0.09 ml) was added to a stirred solution of7-difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic acid(0.15 g) in dry dichloromethane (20 ml) at room temperature under a drynitrogen atmosphere. N,N-dimethylformamide (catalytic amount) was addedand the reaction allowed to stir for 2 hours. The solvent was removed invacuo to furnish the corresponding acid chloride as a yellow oil.

[0172] 3,5-Dimethylisoxazol-4-ylamine (0.11 g) was added to a stirredsolution of the acid chloride in dry dichloromethane (30 ml) at roomtemperature under a dry nitrogen atmosphere. Triethylamine (0.14 ml) wasadded and the reaction allowed to stir at room temperature for 2 hours.The reaction was washed with water (30 ml) and 1N hydrochloric acid (30ml). The organic phase was dried over magnesium sulphate, filtered andpreadsorbed onto silica. Purification by column chromatography on silicaeluting with 30% heptane in ethyl acetate yielded the title compound asa white solid (0.16 g).

[0173] TLC R_(f) 0.17 (50% ethyl acetate in heptane)

[0174] Mp 155.5-156.5° C.

[0175] The following compounds were prepared in a similar manner.

EXAMPLE 9 7-Methoxy-2-(tetrahydrofuran-2-yl)-benzofuran-4-carboxylicacid (3,5-dimethylisoxazol-4-yl)-amide

[0176] Starting from7-methoxy-2-(tetrahydrofuran-2-yl)-benzofuran-4-carboxylic acid (262 mg)and 3,5-dimethylisoxazol-4-ylamine (120 mg). Purification by columnchromatography on silica eluting with 30% ethyl acetate in hexaneafforded the title compound as an off-white solid (238 mg).

[0177] TLC R_(f) 0.36 (50% ethyl acetate in hexane)

[0178] Mass spectrum m/z 357 [M+H].

EXAMPLE 10 7-Methoxy-2-methoxymethylbenzofuran-4-carboxylic acid(3,5-dimethylisoxazol-4-yl)-amide

[0179] Starting from 7-methoxy-2-methoxymethylbenzofuran-4-carboxylicacid (0.19 g) and 3,5-dimethylisoxazol-4-ylamine (88 mg). Purificationby column chromatography on silica eluting with ethyl acetate affordedthe title compound as a cream solid (0.18 g).

[0180] TLC R_(f) 0.17 (5% methanol in dichloromethane)

[0181] Mp 168.5-169.5° C.

EXAMPLE 11 7-Methoxy-2-methoxymethylbenzofuran-4-carboxylic acid(4-chloro-2-methyl-2H-pyrazol-3-yl)-amide

[0182] Starting from 7-methoxy-2-methoxymethylbenzofuran-4-carboxylicacid (0.14 g) and 4-chloro-2-methyl-2H-pyrazol-3-ylamine (78 mg).Purification by column chromatography on silica eluting with 50%-75%ethyl acetate in hexane afforded the title compound as an off whitesolid (34 mg).

[0183] TLC R_(f) 0.57 (ethyl acetate)

[0184] Mp 158-160° C.

EXAMPLE 12 7-Methoxy-2-methoxymethylbenzofuran-4-carboxylic acid(2-methyl-2H-pyrazol-3-yl)-amide

[0185] Starting from 7-methoxy-2-methoxymethylbenzofuran-4-carboxylicacid (93 mg) and 2-methyl-2H-pyrazol-3-ylamine (40 mg). Purification bycolumn chromatography on silica eluting with ethyl acetate afforded thetitle compound as a white solid (43 mg).

[0186] TLC R_(f) 0.4 (ethyl acetate).

[0187] Mp 148-150° C.

EXAMPLE 13 7-Methoxy-2-methoxymethylbenzofuran-4-carboxylic acid(2-ethyl-2H-pyrazol-3-yl)-amide

[0188] Starting from 7-methoxy-2-methoxymethylbenzofuran-4-carboxylicacid (0.15 g) and 2-ethyl-2H-pyrazol-3-ylamine (85 mg). Purification bycolumn chromatography on silica eluting with 50% ethyl acetate inheptane increasing to ethyl acetate afforded the title compound as ayellow solid (35 mg).

[0189] TLC R_(f) 0.35 (ethyl acetate)

[0190] Mp 97-99° C.

EXAMPLE 14 7-Methoxy-2-methoxymethylbenzofuran-4-carboxylic acid(2,4-dimethyl-2H-pyrazol-3-yl)-amide

[0191] Starting from 7-methoxy-2-methoxymethylbenzofuran-4-carboxylicacid (0.1 g) and 2,4-dimethyl-2H-pyrazol-3-ylamine (56 mg). Purificationby column chromatography on silica eluting with 20% heptane in ethylacetate and gradient preparative HPLC on a Phenomenex LUNA(2)™ C18column eluting with 0.05% trifluoroacetic acid in 20%-65% acetonitrilein water gave the title compound as a pale yellow solid (39 mg).

[0192] TLC R_(f) 0.33 (ethyl acetate)

[0193] Mass spectrum m/z 328 [M−H].

EXAMPLE 15 7-Difluoromethoxy-2-methoxymethylbenzofuran-4-carboxylic acid(3,5-dimethylisoxazol-4-yl)-amide

[0194] Cyanuric chloride (19 mg) and triethylamine (0.05 ml) were addedto a stirred solution of7-difluoromethoxy-2-methoxymethylbenzofuran-4-carboxylic acid (85 mg) indry dichloromethane at room temperature under a dry nitrogen atmosphere.After stirring for 20 minutes 3,5-dimethylisoxazol-4-ylamine (42 mg) wasadded and the reaction left overnight. The reaction was mixture waspreadsorbed onto silica. Purification by column chromatography on silicaeluting with 30% ethyl acetate in hexane gave the title compound as acream solid (33 mg)

[0195] TLC R_(f) 0.52 (50% ethyl acetate in hexane)

[0196] Mass spectrum m/z 367 [M+H].

1. A compound of the formula

wherein R₁ is C₁₋₃ alkyl optionally substituted with one or morefluorines; R₂ is CH₂OCH₃ or 2 or 3-tetrahydrofuranyl; R₃ is a pyrazole,imidazole or isoxazole group of partial formula (A), (B) or (C)

R₄ is C₁₋₃ alkyl; and R₅ and R₆, which may be the same or different,each represents C₁₋₃ alkyl, halogen, CF₃ or CN; or apharmaceutically-acceptable salt thereof.
 2. A compound of claim 1 ,wherein R₁ is CH₃ or CHF₂.
 3. A compound of claim 1 or claim 2 , whereinR₃ is a pyrazole or isoxazole group.
 4. A compound of claim 3 , whereinR₃ is a pyrazole group, R₄ is CH₃ and R₅ is CN, CH₃, Cl or CF₃.
 5. Acompound of claim 3 , wherein R₃ is an isoxazole group, R₅ is CH₃, CF₃or CN and R₅ is CH₃, CF₃ or CN.
 6. A compound of claim 1 , selected from7-methoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic acid(3,5-dimethylisoxazol-4-yl)-amide,7-difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic acid(4-cyano-2-methyl-2-H-pyrazol-3-yl)-amide,7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid(5-cyano-3-methyl-3H-imidazol-4-yl)-amide7-difluoromethoxy-2-methoxymethylbenzofuran-4-carboxylic acid(4-cyano-2-methyl-2-pyrazol-3-yl)-amide,7-methoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic acid(4-cyano-2-methyl-2-pyrazol-3-yl)-amide,7-methoxy-2-(tetrahydrofuran-2-yl)-benzofuran-4-carboxylic acid(4-cyano-2-methyl-2-pyrazol-3-yl)-amide,7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid(4-cyano-2-methyl-2-pyrazol-3-yl)-amide,7-difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic acid(3,5-dimethylisoxazol-4-yl)-amide,7-methoxy-2-(tetrahydrofuran-2-yl)-benzofuran-4-carboxylic acid(3,5-dimethylisoxazol-4-yl)-amide,7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid(3,5-dimethylisoxazol-4-yl)-amide,7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid(4-chloro-2-methyl-2H-pyrazol-3-yl)-amide,7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid(2-methyl-2H-pyrazol-3-yl)-amide,7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid(2-ethyl-2H-pyrazol-3-yl)-amide,7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid(2,4-dimethyl-2H-pyrazol-3-yl)-amide, and7-difluoromethoxy-2-methoxymethylbenzofuran-4-carboxylic acid(3,5-dimethylisoxazol-4-yl)-amide.
 7. A composition for use in therapy,comprising a compound of any preceding claim and a pharmaceuticallyacceptable carrier or diluent.
 8. Use of a compound of any of claims 1to 6 , for the manufacture of a medicament for use in the treatment of adisease state that is capable of being modulated by inhibition ofphosphodiesterase IV or Tumour Necrosis Factor, or that is apathological condition associated with a function of phosphodiesteraseIV, eosinophil accumulation or a function of the eosinophil.
 9. The useof claim 8 , wherein the disease state is an inflammatory disease orautoimmune disease.
 10. The use of claim 8 , wherein the disease stateis selected from asthma, chronic bronchitis, chronic pulmonaryinflammatory disease, chronic obstructive airways disease, atopicdermatitis, allergic rhinitis, psoriasis, arthritis, rheumatoidarthritis, joint inflammation, ulcerative colitis, Crohn's disease,atopic eczema, stroke, bone resorption disease, multiple sclerosis andinflammatory bowel disease.
 11. The use of claim 8 , wherein the diseasestate is selected from urticaria, allergic conjunctivitis, vernalconjunctivitis, inflammation of the eye, allergic responses in the eye,eosinophilic granuloma, gouty arthritis and other arthritic conditions,adult respiratory distress syndrome, diabetes insipidus, keratosis,cerebral senility, multi-infarct dementia, senile dementia, memoryimpairment associated with Parkinson's disease, depression, cardiacarrest, intermittent claudication, rheumatoid spondylitis,osteoarthritis, sepsis, septic shock, endotoxic shock, gram negativesepsis, toxic shock syndrome, acute respiratory distress syndrome,cerebral malaria, silicosis, pulmonary sarcoidosis, reperfusion injury,graft vs host reaction, allograft rejection, infection-related fever ormyalgia, malaria, HIV, AIDS, ARC, cachexia, keloid formation, scartissue formation, pyresis, systemic lupus erythematosus, type 1 diabetesmellitus, Bechet's disease, anaphylactoid purpura nephritis, chronicglomerulonephritis, leukaemia, tarditive dyskinesia, yeast or fungalinfection, conditions requiring gastroprotection, and neurogenicinflammatory disease associated with irritation and pain.
 12. The use ofclaim 8 , wherein the disease state is asthma.
 13. The use of claim 8 ,wherein the disease state is chronic obstructive airways disease orchronic bronchitis.